DESCRIPTION: HIV-associated nephropathy (HIVAN) is a renal disease almost exclusively seen in people of African ancestry. It is caused directly by the infection and injury of podocytes and renal tubular epithelial cells (RTEc) by HIV-1. While the mechanism for renal epithelial cell infection by HIV-1 in vivo has not been elucidated, endogenous host factors are believed to play a crucial role in this process. Additionally variants in the APOL1 gene (G1/G2) were recently identified as a major risk for developing HIVAN in adults. Identifying the mechanism by which APOL1 variants precipitate the development of HIVAN can provide insights into the underlying mechanism involved in the pathogenesis of HIVAN. Recently we identified tumor necrosis factor alpha (TNF-a) as a critical host factor that facilitates the infection of podocytes cultured from children with HIVAN. TNF-a, in presence of infectious HIV-1, also increases the expression of ApoL-1, a protein that at physiological levels regulates autophagy. We hypothesize that TNF-a is the host factor that plays a critical role in the pathogenesis of childhood HIVAN by facilitatin infection of renal epithelial cells and increasing ApoL-1expression. In HIV-1 infected podocytes, over expression of the APOL1 risk variants, tip the balance to increased podocyte death triggering renal epithelial injury, which precipitates in the development of HIVAN. This hypothesis will be tested in three aims. In aim 1, we will define how TNF-a affects viral entry and infection of podocytes and RTEc cultured from children with HIVAN, and identify the TNF-a domain involved in this process. In aim 2, we will determine how ApoL-1 modulates the survival of infected podocytes in culture by interacting with TNF-a, viral proteins, and endocytic or autophagic pathways for viral entry and degradation. In aim 3, we will define how APOL1 and TNF-a affect the renal outcome of young wild type and HIV-Tg26 mice, and validate relevant clinical findings in renal sections, cells, and urine samples collected from children with HIVAN. These experiments will generate highly relevant clinical information to understand how children develop HIVAN.